Is TBX4 p.Phe207= (c.621C>T) pathogenic?

TBX4 p.Phe207= (c.621C>T) is classified Likely benign in TBX4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-17). Ultra-rare (popmax 0.0137%, nfe).

How common is TBX4 p.Phe207= (c.621C>T) in the general population?

TBX4 p.Phe207= (c.621C>T) is ultra-rare (popmax 0.0137%, nfe) (gnomAD).

TBX4 p.Phe207=

c.621C>T · rs150224277 · VCV3056050

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.94	GERP -5.1, phastCons 0.006
Overall
CADD	8.055	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0137% European (non-Finnish) · 162/1,180,044 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.0131% 211/1,614,060 alleles · ultra-rare exomes 189/1,461,890 · genomes 22/152,170 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0531%	1,883
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)grpmax	0.0137%	7,284
East Asian	0.0111%	8,978
African / African-American	0.00133%	74,908

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TBX4
Protein: p.Phe207=
Coding: c.621C>T
MANE Select: NM_001321120
dbSNP: rs150224277
Type: single nucleotide variant
Location: chr17:61478698 (GRCh38)
Gene constraint: LOEUF 0.379 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.96
Residue 207: a DNA-binding region; a UniProt-annotated variant site (in pappas; also responsible for ischiocoxopodopatellar syndrome in heterozygous carriers; no detectable protein expression in homozygous patient cells)

Full TBX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TBX4 c.1021+1G>A Pathogenic/Likely pathogenic ★★ same type
TBX4 c.702+1G>A Pathogenic/Likely pathogenic ★★ same type
TBX4 p.Arg250Trp Pathogenic ★★ same type
TBX4 p.Arg261Ter Pathogenic ★★ same type
TBX4 p.Arg340Ter Pathogenic/Likely pathogenic ★★ same type
TBX4 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same type
TBX4 p.Arg527Ter Pathogenic ★★ same type
TBX4 p.Asp329Tyr Pathogenic/Likely pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tbx4-p-phe207 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown